Elsevier

Seminars in Oncology

Volume 40, Issue 1, February 2013, Pages 100-108
Seminars in Oncology

The evolving landscape of neuroendocrine tumors
The Management of Extrapulmonary Poorly Differentiated (High-Grade) Neuroendocrine Carcinomas

https://doi.org/10.1053/j.seminoncol.2012.11.011Get rights and content

Extrapulmonary high-grade neuroendocrine carcinomas (HGNECs) are rare but aggressive tumors that can be found throughout the body but are most commonly located in the gastrointestinal (GI) and the genitourinary tracts. They also have been described in the thymus, breast, oropharynx, and other organs. Due to the rarity of these tumors, publications are limited to small series and, as a result, treatment regimens are extrapolated from more robust data published on pulmonary HGNECs. For metastatic disease, platinum-based chemotherapy is the backbone of treatment. For localized disease, there are currently no standard treatment algorithms. Surgical resection with low morbidity is a reasonable treatment option, particularly in lesions where the possibility of obstruction is high. However, given the very high risk of disease recurrence, a multimodality approach with either neoadjuvant or adjuvant therapy is warranted. For locally advanced disease, chemoradiation should be considered, incorporating a platinum-based regimen when possible. Chemoradiation also should be considered when primary resection would lead to significant morbidity, such as with rectal, pancreas, and esophageal HGNECs.

Section snippets

Incidence and Diagnosis

HGNECs of the GI tract are rare tumors comprising less then 1% of all GI tract malignancies. They have been described in the esophagus, stomach, gallbladder and bile ducts, pancreas, liver, small and large bowel, and anus.18 They present in the same manner as the more frequently found adenocarcinomas and squamous cell carcinomas, but as they are almost always metastatic at presentation, patients often can present with systemic symptoms such as fever, weight loss, anorexia, pain, or jaundice.19,

HGNECs of the Genitourinary Tract

HGNECs of the genitourinary tract are rare tumors accounting for less than 1% of tumors found in these organs.46, 47, 48 They are most commonly described in the cervix, bladder, and prostate but also have been described in the uterus, vagina, vulva, testis, and kidney (Table 3). They often present with vaginal bleeding, hematuria, or lower abdominal pain. As with most HGNECs, a high proportion of patients present with metastatic disease. Diagnosis is made by biopsy of the lesion, either by

Other Extrapulmonary HGNECs

HGNECs also have been described in the thymus, breast, oropharynx, and other organs (Table 4).57, 58, 59, 60 Clinical presentation corresponds to that of the more common tumor types arising from the corresponding organs. Treatment follows the same paradigm as other extrapulmonary HGNECs as previously discussed. Brain metastases have been reported in head and neck HGNECs more frequently then other extrapulmonary HGNECs, thus a staging brain magnetic resonance image and possibly prophylactic

Genetics and Future Directions

Few studies have attempted to characterize the molecular features of extrapulmonary HGNEC (ie, loss of tumor-suppressor genes and activation of oncogenes). Most of the published data are focused on the small cell variant of HGNEC. These studies demonstrate that the genetic alterations mimic that of the pulmonary type of HGNEC. Tumors are characterized by p53 overexpression, Rb loss, and telomerase activation; KRAS mutations are rarely found. Loss of the adhesion molecules E-cadherin, alpha

Conclusions

Extrapulmonary HGNECs pose a significant challenge because they are rare, heterogeneous tumors that are aggressive and rarely cured. Platinum-based systemic chemotherapy should be the backbone of treatment and plays a role in controlling local and distant disease. Surgery and or radiation for localized disease is reasonable; however, the risk of metastatic spread is extremely high and needs to be considered before any local approach is considered. A crucial challenge is to select the optimal

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